Gametocytocidal and Transmission-blocking Efficacy of PQ in Combination With AL and TQ in Combination With SPAQ in Mali

Full protocol available on request.

• Artemether-lumefantrine (Drug), also known as Riamet: Tablets containing 20/80 mg artemether and 120/480 mg lumefantrine will be administered according to weight as per manufacturer guidelines.
• Primaquine Phosphate (Drug), also known as Primaquine: The single dose of 0.25mg/kg PQ will be administered in an aqueous solution, according to a standard operating procedure (SOP) provided by the manufacturer.
• Sulphadoxine-pyrimethamine with amodiaquine (Drug), also known as Supyra: Sulfadoxine/pyrimethamine tablets contain 500mg sulfadoxine and 25mg pyrimethamine. Amodiaquine tablets contain 150mg amodiaquine (as hydrochloride). Tablets will be administered according to weight as per manufacturer guidelines.
• Tafenoquine (Drug), also known as Arakoda: 100mg tafenoquine tablets are prepared into a 1mg/mL solution in water. Solution will be given according to weight as indicated per treatment arm in 5kg bands.

Primary outcomes

• Change in mosquito infection rate assessed through membrane feeding assays (day 2 and day 7) [3 days (days 0, 2 and 7): 7 day span]: Within person percent change (presented as percent reduction) in mosquito infection rate in infectious individuals from baseline (day 0, pre-treatment) to day 2 post treatment in the AL and AL-PQ arms, and day 7 post-treatment in the SPAQ and SPAQ-TQ.

Secondary outcomes

• Change in mosquito infection rate assessed through membrane feeding assays (all timepoints) [7 days (day 0, day 2, day 5, day 7, day 14, day 21, day 28): 28 day span]: Within person percent change (presented as percent reduction) in mosquito infection rate from baseline to all feeding time-points, with comparison within and between arms.
• Mosquito infection rate assessed through membrane feeding assays [7 days (day 0, day 2, day 5, day 7, day 14, day 21, day 28): 28 day span]: Mosquito infection rate at all feeding time-points, with comparison within treatment arms compared to baseline, and between arms.
• Human infectivity to locally reared mosquitoes assessed through membrane feeding assays [7 days (day 0, day 2, day 5, day 7, day 14, day 21, day 28): 28 day span]: Infectivity to mosquitoes at all feeding time-points, with comparison within treatment arms compared to baseline, and between arms.
• Mosquito infection density assessed through membrane feeding assays [7 days (day 0, day 2, day 5, day 7, day 14, day 21, day 28): 28 day span]: Oocyst intensity (in all/all infected mosquitoes) at all feeding time-points, with comparison within treatment arms compared to baseline, and between arms.
• Gametocyte infectivity [7 days (day 0, day 2, day 5, day 7, day 14, day 21, day 28): 28 day span]: Infectiousness to mosquitoes for a given gametocyte density (measured as mosquito infection rate/gametocyte) at all feeding time-points, with comparison within treatment arms compared to baseline, and between arms.
• Asexual/sexual stage parasite prevalence [7 days (day 0, day 2, day 5, day 7, day 14, day 21, day 28): 28 day span]: Male and female gametocyte prevalence at all time-points, determined by microscopy or molecular assays, with comparison within treatment arms compared to baseline, and between arms. Asexual and total parasite prevalence at all time-points, determined by microscopy or molecular assays, with comparison within treatment arms compared to baseline, and between arms.
• Asexual/sexual stage parasite density [7 days (day 0, day 2, day 5, day 7, day 14, day 21, day 28): 28 day span]: Male and female gametocyte density at all time-points, determined by microscopy or molecular assays, with comparison within treatment arms compared to baseline, and between arms. Asexual and total parasite density at all time-points, determined by microscopy or molecular assays, with comparison within treatment arms compared to baseline, and between arms.
• Sexual stage parasite sex ratio [7 days (day 0, day 2, day 5, day 7, day 14, day 21, day 28): 28 day span]: Male and female gametocyte sex ratio (proportion male) at all time-points, determined by microscopy or molecular assays, with comparison within treatment arms compared to baseline, and between arms.
• Sexual stage parasite circulation time [7 days (day 0, day 2, day 5, day 7, day 14, day 21, day 28): 28 day span]: Gametocyte circulation time (cumulative), determined by microscopy or molecular assays, compared within and between treatment arms.
• Sexual stage parasite area under the curve (AUC) [7 days (day 0, day 2, day 5, day 7, day 14, day 21, day 28): 28 day span]: Gametocyte area under the curve (cumulative), determined by microscopy or molecular assays, compared within and between treatment arms.
• Haemoglobin density [8 days (day 0, day 1, day 2, day 5, day 7, day 14, day 21, day 28): 28 day span]: Haemoglobin density (g/dL) at all time-points, with comparison within treatment arms compared to baseline, and between arms.
• Change in haemoglobin density [8 days (day 0, day 1, day 2, day 5, day 7, day 14, day 21, day 28): 28 day span]: Within person percent change (presented as percent reduction) in haemoglobin density (g/dL) from baseline to all time-points, with comparison within and between arms.
• Methaemoglobin density [8 days (day 0, day 1, day 2, day 5, day 7, day 14, day 21, day 28)]: Methaemoglobin density (g/dL) at all time-points, with comparison within treatment arms compared to baseline, and between arms.
• Change in methaemoglobin density [8 days (day 0, day 1, day 2, day 5, day 7, day 14, day 21, day 28): 28 day span]: Within person percent change (presented as percent reduction) in methaemoglobin density (g/dL) from baseline to all time-points, with comparison within and between arms.
• Incidence of adverse events [8 days (day 0, day 1, day 2, day 5, day 7, day 14, day 21, day 28): 28 day span]: The frequency and prevalence of adverse events (all AE's, treatment related AE's, and haematological AE's) observed up to and including day 2, 7, and 14 post-treatment, and at all timepoints.

Other outcomes

• Parasite genomic and transcriptomic variation assessed in RNA [7 days (day 0, day 2, day 5, day 7, day 14, day 21, day 28): 28 day span]: Parasite genotype and transcriptional analysis at baseline and at post-treatment timepoints.
• The impact of plasma biomarkers on malaria transmission efficiency [7 days (day 0, day 2, day 5, day 7, day 14, day 21, day 28): 28 day span]: Plasma biomarkers (antibodies and parasite protein) at baseline and at post-treatment timepoints.
• Human genomic variation analysis and association with parasite measure [day 0]: Human genotype analysis at baseline (G6PD, CYP2D6, and HBB type)
• ALT/AST/Creatine density [8 days (day 0, day 1, day 2, day 5, day 7, day 14, day 21, day 28): 28 day span]: ALT/AST/Creatine density at all time-points with comparison within treatment arms compared to baseline, and between arms.

Sex: All, ages: 10 Years to 50 Years, accepts healthy volunteers

Inclusion Criteria:

* Age ≥ 10 years and ≤ 50 years
* G6PD-normal defined by Carestart rapid diagnostic test or the OSMMR2000 G6PD qualitative test
* Absence of symptomatic falciparum malaria, defined by fever on enrolment
* Presence of P. falciparum gametocytes on thick blood film at a density >16 gametocytes/μL (i.e. ≥ gametocytes recorded in the thick film against 500 white blood cells)
* Absence of other non-P. falciparum species on blood film
* Hemoglobin ≥ 10 g/dL
* Individuals weighing < = 80 kg
* No evidence of acute severe or chronic disease
* Written, informed consent

Exclusion Criteria:

* Women who are pregnant or lactating (tested at baseline). Urine and/or serum pregnancy testing (β-hCG) will be used.
* Detection of a non-P. falciparum species by microscopy
* Previous reaction to study drugs / known allergy to study drugs
* Signs of severe malaria, including hyperparasitemia (defined as asexual parasitemia > 100,000 parasites / μL)
* Signs of acute or chronic illness, including hepatitis
* The use of other medication (except for paracetamol and/or aspirin)
* Use of antimalarial drugs over the past 7 days (as reported by the participant)
* Clinically significant illness (intercurrent illness e.g., pneumonia, pre-existing condition e.g., renal disease, malignancy or conditions that may affect absorption of study medication e.g., severe diarrhea or any signs of malnutrition as defined clinically)
* Signs of hepatic injury (such as nausea and/or abdominal pain associated with jaundice) or known severe liver disease (i.e., decompensated cirrhosis, Child Pugh stage B or C)
* Signs, symptoms or known renal impairment
* Clinically significant abnormal laboratory values as determined by history, physical examination or routine blood chemistries and hematology values (laboratory guideline values for exclusion are hemoglobin < 10 g/dL, platelets < 50,000/μl, White Blood Cell count (WBC) < 2000/μl, serum creatinine >2.0mg/dL, or ALT or AST more than 3 times the upper limit of normal for age.
* Blood transfusion in the last 90 days.
* Consistent with the long half-life of tafenoquine, effective contraception should be continued for 5 half-lives (3 months) after the end of treatment.
* History of psychiatric disorders

• Results publication: Mahamar A, Smit MJ, Sanogo K, Sinaba Y, Niambele SM, Sacko A, Dicko OM, Diallo M, Maguiraga SO, Sankare Y, Keita S, Samake S, Dembele A, Lanke K, Ter Heine R, Bradley J, Dicko Y, Traore SF, Drakeley C, Dicko A, Bousema T, Stone W. Artemether-lumefantrine with or without single-dose primaquine and sulfadoxine-pyrimethamine plus amodiaquine with or without single-dose tafenoquine to reduce Plasmodium falciparum transmission: a phase 2, single-blind, randomised clinical trial in Ouelessebougou, Mali. Lancet Microbe. 2024 Jul;5(7):633-644. doi: 10.1016/S2666-5247(24)00023-5. Epub 2024 May 2. PMID 38705163

• Alassane Dicko, Principal investigator, Malaria Research and Training Center, Bamako, Mali